This invention relates to a novel group of pyrazole compounds, compositions and methods for treating p38 kinase mediated disorders.
Mitogen-activated protein kinases (MAP) is a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals including nutritional and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines. The p38 MAP kinase group is a MAP family of various isoforms, including p38xcex1, p38xcex2 and p38xcex3, and is responsible for phosphorylating and activating transcription factors (e.g. ATF2, CHOP and MEF2C) as well as other kinases (e.g. MAPKAP-2 and MAPKAP-3). The p38 isoforms are activated by bacterial lipopolysaccharide, physical and chemical stress and by pro-inflammatory cytokines, including tumor necrosis factor (TNF-xcex1) and interleukin-1 (IL-1). The products of the p38 phosphorylation mediate the production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2.
TNF-xcex1 is a cytokine produced primarily by activated monocytes and macrophages. Excessive or unregulated TNF production has been implicated in mediating a number of diseases. Recent studies indicate that TNF has a causative role in the pathogenesis of rheumatoid arthritis. Additional studies demonstrate that inhibition of TNF has broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.
TNF has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
IL-8 is another pro-inflammatory cytokine, which is produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes, and is associated with conditions including inflammation.
IL-1 is produced by activated monocytes and macrophages and is involved in the inflammatory response. IL-1 plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption.
TNF, IL-1 and IL-8 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.
Various pyrazoles have previously been described. U.S. Pat. No. 4,000,281, to Beiler and Binon, describes 4,5-aryl/heteroaryl substituted pyrazoles with antiviral activity against both RNA and DNA viruses such as myxoviruses, adenoviruses, rhinoviruses, and various viruses of the herpes group. WO 92/19615, published Nov. 12, 1992, describes pyrazoles as novel fungicides. U.S. Pat. No. 3,984,431, to Cueremy and Renault, describes derivatives of pyrazole-5-acetic acid as having anti-inflammatory activity. Specifically, [1-isobutyl-3,4-diphenyl-1H-pyrazol-5-yl]acetic acid is described. U. S. Pat. No. 3,245,093 to Hinsgen et al, describes a process for preparing pyrazoles. WO 83/00330, published Feb. 3, 1983, describes a new process for the preparation of diphenyl-3,4-methyl-5-pyrazole derivatives. WO 95/06036, published Mar. 2, 1995, describes a process for preparing pyrazole derivatives. U.S. Pat. No. 5,589,439, to T. Goto, et al., describes tetrazole derivatives and their use as herbicides. EP 515041 describes pyrimidyl substituted pyrazole derivatives as novel agricultural fungicides. Japanese Patent 4,145,081 describes pyrazolecarboxylic acid derivatives as herbicides. Japanese Patent 5,345,772 describes novel pyrazole derivatives as inhibiting acetylcholinesterase.
Pyrazoles have been described for use in the treatment of inflammation. Japanese Patent 5,017,470 describes synthesis of pyrazole derivatives as anti-inflammatory, anti-rheumatic, anti-bacterial and anti-viral drugs. EP 115640, published Dec. 30, 1983, describes 4-imidazolyl-pyrazole derivatives as inhibitors of thromboxane synthesis. 3-(4-Isopropyl-1-methylcyclohex-1-yl)-4-(imidazol-1-yl)-1H-pyrazole is specifically described. WO 97/01551, published Jan. 16, 1997, describes pyrazole compounds as adenosine antagonists. 4-(3-Oxo-2,3-dihydropyridazin-6-yl)-3-phenylpyrazole is specifically described. U.S. Pat. No. 5,134,142, to Matsuo et al. describes 1,5-diaryl pyrazoles as having anti-inflammatory activity.
U.S. Pat. No. 5,559,137 to Adams et al, describes novel pyrazoles (1,3,4,-substituted) as inhibitors of cytokines used in the treatment of cytokine diseases. Specifically, 3-(4-fluorophenyl)-1-(4-methylsulfinylphenyl)-4-(4-pyridyl)-5H-pyrazole is described. WO 96/03385, published Feb. 8, 1996, describes 3,4-substituted pyrazoles, as having anti-inflammatory activity. Specifically, 4-[1-ethyl-4-(4-pyridyl)-5-trifluoromethyl-1H-pyrazol-3-yl]benzenesulfonamide is described.
The invention""s pyrazolyl compounds are found to show usefulness as p38 kinase inhibitors.
A class of substituted pyrazolyl compounds useful in treating p38 mediated disorders is defined by Formula I: 
wherein
R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, heterocyclylalkylene, alkoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, mercaptoalkyl, mercaptoaryl, mercaptoheterocyclyl, alkylthioalkylene, arylthioalkylene, amino, alkylamino, arylamino, aminoalkyl, aminoaryl, alkylaminoalkylene, and heterocyclylalkylene; and
Q is selected from oxy, thio, alkylene, alkenylene, alkynylene, sulfinyl, sulfonyl, 
xe2x80x83wherein 
represents a four to eight membered ring heterocyclylidenyl comprising one or more heteroatoms selected from oxygen, sulfur and nitrogen; and
wherein n is an integer from 1 to 7; and
R2 is aryl optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heterocyclyloxy, aralkoxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, amino, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, aminoalkyl, aminocarbonyl, cyano, hydroxyl, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, formyl, nitro, nitroalkyl, alkylcarbonylamino, arylcarbonylamino, haloalkylsulfinyl, haloalkylsulfonyl, alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, and haloalkyl; and
R3 is heteroaryl optionally substituted with one or more radicals independently selected from halo, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, aminocarbonyl, cyano, hydroxyl, alkoxycarbonyl, formyl, aralkyl, aralkyloxy, aralkylthio, aralkylamino, aminosulfonyl, alkylamino, nitro, arylamino, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl and alkylcarbonyl; and
R4 is selected from hydrido, alkyl, aryl, haloalkyl, heterocyclyl, cycloalkyl, alkenyl, cycloalkenyl, alkoxy, alkylthio, arylthio, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkylene, heterocyclylalkyl, amino, alkylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, heterocyclylaminoalkyl, and aminoheterocyclylamino; wherein the aryl, heterocyclyl, cycloalkyl, cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, amino, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aralkoxy, haloalkyl, and alkylamino; and wherein the amino radicals of the heterocylcylalkylamino and heterocylcylaminoalkyl group are optionally substituted with one or more alkyl; and
R6 is selected from hydrido, alkyl, alkenyl, and alkynyl; and
R7 and R8 are independently selected from hydrido, alkyl, alkenyl, and alkynyl, or together form a carbocyclic or heterocyclic ring having three to eight members; and
R9 is selected from hydrido, alkyl, alkenyl, and alkynyl; and
R10 is selected from hydrido, alkyl, alkenyl, and alkynyl; and
R11 is selected from hydrido, alkyl, alkenyl, and alkynyl; and
R12 is selected from hydrido and alkyl; or
a pharmaceutically-acceptable salt or tautomer thereof.
Compounds of Formula I would be useful for, but not limited to, the treatment of any disorder or disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated TNF or p38 kinase production by such mammal. Accordingly, the present invention provides a method of treating a cytokine-mediated disease which comprises administering an effective cytokine-interfering amount of a compound of Formula I, or a pharmaceutically acceptable salt or tautomer thereof.
Compounds of Formula I would be useful for, but not limited to, the treatment of inflammation in a subject, and for use as antipyretics for the treatment of fever. Compounds of the invention would be useful to treat arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions. Such compounds would be useful for the treatment of pulmonary disorders or lung inflammation, including adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis, and chronic pulmonary inflammatory disease. The compounds are also useful for the treatment of viral and bacterial infections, including sepsis, septic shock, gram negative sepsis, malaria, meningitis, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, and herpesvirus. The compounds are also useful for the treatment of bone resorption diseases, such as osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune disease including graft vs. host reaction and allograft rejections, cardiovascular diseases including atherosclerosis, thrombosis, congestive heart failure, and cardiac reperfusion injury, renal reperfusion injury, liver disease and nephritis, and myalgias due to infection. The compounds are also useful for the treatment of influenza, multiple sclerosis, cancer, diabetes, systemic lupus erthrematosis (SLE), skin-related conditions such as psoriasis, eczema, burns, dermatitis, keloid formation, and scar tissue formation. Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn""s disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue. Compounds of the invention also would be useful for treatment of angiogenesis, including neoplasia; metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemaginomas, including invantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; diabetic nephropathy and cardiomyopathy; and disorders of the female reproductive system such as endometriosis. The compounds of the invention may also be useful for preventing the production of cyclooxygenase-2.
Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
The present compounds may also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatories, such as together with steroids, cyclooxygenase-2 inhibitors, NSAIDs, DMARDS, immunosuppressive agents, 5-lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors.
As used herein, the term xe2x80x9cTNF mediated disorderxe2x80x9d refers to any and all disorders and disease states in which TNF plays a role, either by control of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disorder mediated by TNF.
As used herein, the term xe2x80x9cp38 mediated disorderxe2x80x9d refers to any and all disorders and disease states in which p38 plays a role, either by control of p38 itself, or by p38 causing another factor to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to p38, would therefore be considered a disorder mediated by p38.
As TNF-xcex2 has close structural homology with TNF-xcex1 (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, the synthesis of both TNF-xcex1 and TNF-xcex2 are inhibited by the compounds of the present invention and thus are herein referred to collectively as xe2x80x9cTNFxe2x80x9d unless specifically delineated otherwise.
A preferred class of compounds consists of those compounds of Formula I wherein
R1 is selected from hydrido, lower alkyl, lower alkynyl, lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower thioalkyl, lower alkylthioalkylene, amino, lower alkylamino, lower arylamino, lower alkylaminoalkylene, and lower heterocyclylalkylene; and
Q is selected from lower alkylene, lower alkenylene, sulfinyl, sulfonyl, 
xe2x80x83wherein 
represents a four to eight membered ring heterocyclylidenyl comprising one or more heteroatoms selected from oxygen, sulfur and nitrogen; and
wherein n is an integer from 1 to 7; and
R2 is aryl optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, lower aryloxy, lower aralkoxy, amino, hydroxyl, nitro, cyano, lower haloalkyl, lower alkylamino, and lower alkynylamino; and
R3 is selected from 5- to 10-membered heterocyclyl optionally substituted with one or more radicals independently selected from lower alkylthio, lower alkylsulfonyl, aminosulfonyl, halo, lower alkyl, lower alkylsulfinyl, cyano, lower alkoxycarbonyl, aminocarbonyl, formyl, lower aralkyl, lower aralkyloxy, lower aralkylthio, lower aralkylamino, lower alkylcarbonylamino, lower haloalkyl, hydroxyl, lower alkoxy, amino, lower alkylamino, lower aminoalkyl, phenylamino, nitro, halosulfonyl and lower alkylcarbonyl; and
R4 is selected from hydrido, lower alkyl, aryl, lower haloalkyl, 5-10 membered heterocyclyl, lower alkylamino, lower alkynylamino, phenylamino, lower cycloalkyl, lower alkenyl, lower cycloalkenyl, lower alkoxy, lower alkylthio, carboxy, lower alkoxycarbonyl, lower carboxyalkyl, lower alkoxycarbonylalkylene, lower heterocyclylalkyl, lower heterocylcylalkylamino, and lower heterocylcylaminoalkyl; wherein the aryl, 5-10 membered heteroaryl, lower cycloalkyl and lower cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, phenoxy, lower aralkoxy, lower haloalkyl, and lower alkylamino; and wherein the amino radicals of the lower heterocylcylalkylamino and lower heterocylcylaminoalkyl group are optionally substituted with one or more lower alkyl; and
R6 is selected from hydrido, lower alkyl, lower alkenyl, and lower alkynyl; and
R7 and R8 are independently selected from hydrido, lower lower alkyl, lower alkenyl, and lower alkynyl, or together form a carbocyclic or heterocyclic ring having three to eight members; and
R9 is selected from hydrido, lower alkyl, lower alkenyl, and lower alkynyl; and
R10 is selected from hydrido, lower alkyl, lower alkenyl, and lower alkynyl; and
R11 is selected from hydrido, lower alkyl, lower alkenyl, and lower alkynyl; and
R12 is selected from hydrido and lower alkyl; or
a pharmaceutically-acceptable salt or tautomer thereof.
A more preferred class of compounds consists of those compounds of Formula I wherein
R1 is selected from hydrido, lower alkyl, lower alkynyl, lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower thioalkyl, lower alkylthioalkylene, lower alkylaminoalkylene, and lower heterocyclylalkylene; and
Q is selected from lower alkylene, lower alkenylene, 
xe2x80x83wherein 
represents a four to eight membered ring heterocyclylidenyl comprising one or more heteroatoms selected from oxygen, sulfur and nitrogen; and
wherein n is an integer from 1 to 7; and
R2 is aryl optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, lower aryloxy, lower aralkoxy, amino, hydroxyl, nitro, cyano, lower haloalkyl, lower alkylamino, and lower alkynylamino; and
R3 is 6-membered heteroaryl optionally substituted with one or more radicals independently selected from halo, lower alkyl, cyano, phenethyl, benzyl, benzyloxy, benzylthio, benzylamino, phenethylamino, aminocarbonyl, lower alkylcarbonylamino, hydroxyl, amino, lower alkylamino, lower aminoalkyl, and phenylamino; and
R4 is selected from hydrido, lower alkyl, phenyl, lower haloalkyl, 5-10 membered heterocyclyl, lower alkylamino, lower alkynylamino, phenylamino, lower cycloalkyl, lower alkenyl, lower cycloalkenyl, lower alkoxy, lower heterocyclylaminoalkyl, and lower heterocyclylalkylamino; wherein the phenyl, 5-10 membered heteroaryl, lower cycloalkyl and lower cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, phenoxy, lower aralkoxy, lower haloalkyl, amino, hydroxyl, cyano and lower alkylamino; and wherein the amino radicals of lower heterocyclyl alkylamino and lower heterocyclylaminoalkyl are optionally substituted with one or more lower alkyl; and
R6 is selected from hydrido, lower alkyl, lower alkenyl, and lower alkynyl; and
R7 and R8 are independently selected from hydrido, lower lower alkyl, lower alkenyl, and lower alkynyl, or together form a carbocyclic or heterocyclic ring having three to eight members; and
R9 is selected from hydrido, lower alkyl, lower alkenyl, and lower alkynyl; and
R10 is selected from hydrido, lower alkyl, lower alkenyl, and lower alkynyl; and
R11 is selected from hydrido, lower alkyl, lower alkenyl, and lower alkynyl; and
R12 is selected from hydrido and lower alkyl; or
a pharmaceutically-acceptable salt or tautomer thereof.
A class of compounds of particular interest consists of those compounds of Formula I wherein
R1 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, ethynyl, propargyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, morpholinomethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, methylaminomethyl, cyclohexylmethyl, hydroxymethyl, hydroxylethyl, thiomethyl, and methylthiomethyl; and
Q is selected from methylene, ethylene, propylene, ethenylene, propenylenyl 
xe2x80x83wherein 
represents a four to eight membered ring heterocyclylidenyl comprising one or more heteroatoms selected from oxygen, sulfur and nitrogen; and
wherein n is an integer from 1 to 7; and
R2is phenyl optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, ethynylamino, propargylamino, and hydroxyl; and
R3 is selected from pyridyl, pyridium, and pyrimidyl; wherein R3 is optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, ethyl, isopropyl, cyano, aminocarbonyl, methylcarbonylamino, hydroxy, benzyl, phenethyl, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, and amino; and
R4 is selected from hydrido, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, pyridyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, benzofuryl, methoxy, ethoxy, trifluoromethyl, fluoromethyl, methylamino, ethynylamino, propargylamino, piperidinyl, piperazinyl, piperadinylmethyl, piperadinylmethylamino, piperadinylaminomethyl, piperazinylmethyl, piperazinylmethylamino, piperazinylaminomethyl; wherein the phenyl piperadinyl and piperazinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, propargyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, hydroxyl, cyano and dimethylamino; and wherein the amino radicals of piperadinylmethylamino, piperadinylaminomethyl, piperazinylmethylamino, and piperazinylaminomethyl are optionally substituted with one or more methyl; and
R6 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, and isobutyl; and
R7 and R8 are independently selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, and isobutyl, or together form a carbocyclic or heterocyclic ring having three to eight members; and
R9 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, and isobutyl; and
R10 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, and isobutyl; and
R11 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, and isobutyl; and
R12 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, and isobutyl; or
a pharmaceutically-acceptable salt or tautomer thereof.
A class of compounds of specific interest consists of those compounds of Formula I wherein
R1 is hydrido or methyl; and
Q is selected from methylene, ethylene, ethenylene, 
xe2x80x83wherein 
presents a four to eight membered ring heterocyclylidenyl comprising one or more heteroatoms selected from oxygen, sulfur and nitrogen; and
wherein n is an integer from 1 to 3; and
R2 is phenyl optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxyl; and
R3 is pyridyl optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, cyano, benzyl, phenethyl, aminocarbonyl, hydroxyl, dimethylamino, benzylamino, phenethylamino, aminomethyl and amino; and
R4 is selected from hydrido, methyl, ethyl, propyl, propargylamino, and phenyl optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, dimethylamino, ethynylamino and propargylamino; and
R6 is selected from hydrido and methyl; and
R7 and R8 are independently selected from hydrido and methyl; and
R9 is selected from hydrido and methyl; and
R10 is selected from hydrido and methyl; and
R11 is selected from hydrido and methyl; and
R12 is selected from hydrido and methyl; or
a pharmaceutically-acceptable salt or tautomer thereof.
Within Formula I there is a subclass of compounds of high interest represented by Formula II: 
wherein
R1 is selected from hydrido and lower alkyl; and
Q is selected from lower alkylene, lower alkenylene, 
xe2x80x83wherein 
represents a four to eight membered ring heterocyclylidenyl comprising one or more heteroatoms selected from oxygen, sulfur and nitrogen; and
wherein n is an integer from 1 to 4; and
R2 is phenyl optionally substituted with one or more radicals independently selected from halo and lower alkyl; and
R4, R5, R6, R7, R8, R9, R10, Rh11, and R12 are is independently selected from hydrido and lower alkyl; or
a pharmaceutically-acceptable salt or tautomer thereof.
A preferred class of compounds consists of those compounds of Formula II wherein
R1 is selected from hydrido and methyl; and
wherein Q is selected from methylene, ethylene, ethenylene, 
xe2x80x83and 
R2 is phenyl optionally substituted with one or more radicals independently selected from fluoro, chloro and bromo; and
R4 is selected from hydrido, methyl and ethyl; and
R5 is selected from hydrido and methyl; or
a pharmaceutically-acceptable salt or tautomer thereof.
A family of specific compounds of particular interest within Formula I consists of compounds, tautomers and pharmaceutically-acceptable salts thereof as follows:
4-[3-methyl-5-(2-phenylethenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-(2-phenylethyl)-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-[2-(3-fluorophenyl)ethyl]-1H-pyrazol-4-yl]pyridine;
4-[3-[2-(3-fluorophenyl)ethyl]-1H-pyrazol-4-yl]pyridine;
4-[1-methyl-3-[2-(3-fluorophenyl)ethyl]-1H-pyrazol-4-yl]pyridine;
4-[3-[2-(4-chlorophenyl)ethyl]-1H-pyrazol-4-yl]pyridine;
4-[1-methyl-3-[2-(4-chlorophenyl)ethyl]-1H-pyrazol-4-yl]pyridine;
3-methyl-4-[1-methyl-3-[2-(4-chlorophenyl)ethyl]-1H-pyrazol-4-yl]pyridine;
4-[3-[2-(3-chlorophenyl)ethyl]-1H-pyrazol-4-yl]pyridine;
3-methyl-4-[1-methyl-3-[2-(3,4-dichlorophenyl)ethyl]-1H-pyrazol-4-yl]pyridine;
3-methyl-4-[1-methyl-3-[2-(4-chlorophenyl)ethyl] -1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-[2-(3-fluorophenyl)ethenyl]-1H-pyrazol-4-yl]pyridine;
4-[3-[2-(3-fluorophenyl)ethenyl]-1H-pyrazol-4-yl]pyridine;
4-[1-methyl-3-[2-(3-fluorophenyl)ethenyl]-1H-pyrazol-4-yl]pyridine;
4-[3-[2-(4-chlorophenyl)ethenyl]-1H-pyrazol-4-yl-]pyridine;
4-[1-methyl-3-[2-(4-chlorophenyl)ethenyl]-1H-pyrazol-4-yl]pyridine;
3-methyl-4-[1-methyl-3-[2-(4-chlorophenyl)ethenyl]-1H-pyrazol-4-yl]pyridine;
4-[3-[2-(3-chlorophenyl)ethenyl]-1H-pyrazol-4-yl]pyridine;
3-methyl-4-[1-methyl-3-[2-(3,4-dichlorophenyl)ethenyl]-1H-pyrazol-4-yl]pyridine;
3-methyl-4-[1-methyl-3-[2-(4-chlorophenyl)ethenyl]-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-(3-fluorobenzyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(3-fluorobenzyl)-1H-pyrazol-4-yl]pyridine;
4-[1-methyl-3-(3-fluorobenzyl)-1H-pyrazol-4-yl]pyridine;
4-[3-benzyl-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridine;
4-[1-methyl-3-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridine;
3-methyl-4-[1-methyl-3-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(3-chlorobenzyl)-1H-pyrazol-4-yl]pyridine;
3-methyl-4-[1-methyl-3-(3,4-dichlorobenzyl)-1H-pyrazol-4-yl]pyridine;
3-methyl-4-[1-methyl-3-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridine;
(3-fluorophenyl)[3-methyl-4-(4-pyridinyl)-1H-pyrazol-5-yl]methanone;
(3-fluorophenyl)[4-(4-pyridinyl)-1H-pyrazol-3-yl]methanone;
(3-fluorophenyl)[1-methyl-4-(4-pyridinyl)-1H-pyrazol-3-yl]methanone;
phenyl[1-methyl-4-(4-pyridinyl)-1H-pyrazol-3-yl]methanone;
(4-chlorophenyl)[4-(4-pyridinyl)-1H-pyrazol-3-yl]methanone;
(4-chlorophenyl)[1-methyl-4-(4-pyridinyl)-1H-pyrazol-3-yl ]methanone;
(4-chlorophenyl)[1-methyl-4-(3-methyl-4-pyridinyl)-1H-pyrazol-3-yl]methanone;
(3-chlorophenyl)[4-(4-pyridinyl)-1H-pyrazol-3-yl]methanone;
(3,4-dichlorophenyl)[1-methyl-4-(3-methyl-4-pyridinyl)-1H-pyrazol-3-yl]methanone;
(4-chlorophenyl)[1-methyl-4-(3-methyl-4-pyridinyl)-1H-pyrazol-3-yl]methanone;
xcex1-(3-fluorophenyl)-3-methyl-4-(4-pyridinyl)-1H-pyrazole-5-methanol;
xcex1-(3-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-methanol;
xcex1-(3-fluorophenyl)-1-methyl-4-(4-pyridinyl)-1H-pyrazole-3-methanol;
xcex1-phenyl1-methyl-4-(4-pyridinyl)-1H-pyrazole-3-methanol;
xcex1-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-methanol;
xcex1-(4-chlorophenyl)-1-methyl-4-(4-pyridinyl)-1H-pyrazole-3-methanol;
xcex1-(4-chlorophenyl)-1-methyl-4-(3-methyl-4-pyridinyl)-1H-pyrazole-3-methanol;
xcex1-(3-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-methanol;
xcex1-(3,4-dichlorophenyl)-1-methyl-4-(3-methyl-4-pyridinyl)-1H-pyrazole-3-methanol;
xcex1-(4-chlorophenyl)-1-methyl-4-(3-methyl-4-pyridinyl)-1H-pyrazole-3-methanol; and
4-[5-(2-phenylethyl)-1H-pyrazol-4-yl]pyridine.
The term xe2x80x9chydridolxe2x80x9d denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (xe2x80x94CH2xe2x80x94) radical. Where used, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d, xe2x80x9calkylsulfonylxe2x80x9d, xe2x80x9calkoxyalkylxe2x80x9d and xe2x80x9chydroxyalkylxe2x80x9d, xe2x80x9cmercaptoalkylxe2x80x9d, the term xe2x80x9calkylxe2x80x9d embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are xe2x80x9clower alkylxe2x80x9d radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. The term xe2x80x9calkylenexe2x80x9d embraces bridging alkyl radicals. The term xe2x80x9calkenylxe2x80x9d embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are xe2x80x9clower alkenylxe2x80x9d radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, 1-propenyl, allyl, 2-propenyl, butenyl and 4-methylbutenyl. The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9clower alkenylxe2x80x9d, embrace radicals having xe2x80x9ccisxe2x80x9d and xe2x80x9ctransxe2x80x9d orientations, or alternatively, xe2x80x9cExe2x80x9d and xe2x80x9cZxe2x80x9d orientations. The term xe2x80x9calkenylenexe2x80x9d describes bridging alkenyl radicals. The term xe2x80x9calkynylxe2x80x9d embraces linear or branched radicals having at least one carbon-carbon triple bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are xe2x80x9clower alkynylxe2x80x9d radicals having two to about six carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl and propargyl. The term xe2x80x9calkynylenexe2x80x9d describes bridging alkynyl radicals. The term xe2x80x9ccycloalkylxe2x80x9d embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are xe2x80x9clower cycloalkylxe2x80x9d radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term xe2x80x9ccycloalkylalkylenexe2x80x9d embraces alkyl radicals substituted with a cycloalkyl radical. More preferred cycloalkylalkylene radicals are xe2x80x9clower cycloalkylalkylenexe2x80x9d which embrace lower alkyl radicals substituted with a lower cycloalkyl radical as defined above. Examples of such radicals include cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene and cyclohexylmethylene. The term xe2x80x9ccycloalkenylxe2x80x9d embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. When a cycloalkenyl radical embraces partially unsaturated carbocyclic radicals which contain two double bonds but not necessary conjugated, it can be called xe2x80x9ccycloalkyldienylxe2x80x9d. More preferred cycloalkenyl radicals are xe2x80x9clower cycloalkenylxe2x80x9d radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl. The term xe2x80x9chaloxe2x80x9d means halogens such as fluorine, chlorine, bromine or iodine. The term xe2x80x9chaloalkylxe2x80x9d embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. xe2x80x9cLower haloalkylxe2x80x9d embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term xe2x80x9chydroxyalkylxe2x80x9d embraces linear or branched alkyl radicals having one to about ten carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are xe2x80x9clower hydroxyalkylxe2x80x9d radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms xe2x80x9calkoxyxe2x80x9d and xe2x80x9calkyloxyxe2x80x9d embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are xe2x80x9clower alkoxyxe2x80x9d radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term xe2x80x9calkoxyalkylxe2x80x9d embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical to form, for example, monoalkoxyalkyl and dialkoxyalkyl radicals. The xe2x80x9calkoxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkoxyxe2x80x9d radicals.
The term xe2x80x9carylxe2x80x9d alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. More preferred aryl are 6-12 membered aryl. Examples of such radicals include, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heterocyclyloxy, aralkoxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, amino, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, aminoalkyl, aminocarbonyl, cyano, hydroxyl, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, formyl, nitro, nitroalkyl, alkylcarbonylamino, arylcarbonylamino, haloalkylsulfinyl, haloalkylsulfonyl, alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, carboxy, and aralkoxycarbonyl.
The term xe2x80x9cheterocyclylxe2x80x9d embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, which can also be called xe2x80x9cheterocyclylxe2x80x9d, xe2x80x9cheterocycloalkenylxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d correspondingly, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicals may include a pentavalent nitrogen, such as in tetrazolium and pyridinium radicals. The term xe2x80x9cheteroarylxe2x80x9d embraces unsaturated heterocyclyl radicals. Examples of heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyi, etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like. The terms xe2x80x9cheteroaryl and heterocyclylxe2x80x9d also embrace radicals where heterocyclyl radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said heterocyclyl group may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino. The term xe2x80x9cheterocyclylalkylenexe2x80x9d embraces saturated, partially unsaturated and unsaturated heterocyclyl-substituted alkyl radicals. More preferred heterocyclylalkylene radicals are xe2x80x9clower heterocyclylalkylenexe2x80x9d radicals having one to six carbon atoms and a heterocyclyl radical. Examples of such radicals include pyrrolidinylmethyl, pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl group in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.
The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are xe2x80x9clower alkylthioxe2x80x9d radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term xe2x80x9calkylthioalkylenexe2x80x9d embraces radicals containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkylene radicals are xe2x80x9clower alkylthioalkylenexe2x80x9d radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkylene radicals include methylthiomethyl, The term xe2x80x9calkylsulfinylxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms, attached to a divalent xe2x80x94S(xe2x95x90O)xe2x80x94 radical. More preferred alkylsulfinyl radicals are xe2x80x9clower alkylsulfinylxe2x80x9d radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term xe2x80x9csulfonylxe2x80x9d, whether used alone or linked to other terms, such as xe2x80x9calkylsulfonylxe2x80x9d, or xe2x80x9chalosulfonyl,xe2x80x9d denotes the divalent radical, xe2x80x94SO2xe2x80x94. xe2x80x9cAlkylsulfonylxe2x80x9d embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are xe2x80x9clower alkylsulfonylxe2x80x9d radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The xe2x80x9calkylsulfonylxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals. The term xe2x80x9chalosulfonylxe2x80x9d embraces halo radicals attached to a sulfonyl radical. Examples of such halosulfonyl radicals include chlorosulfonyl, and bromosulfonyl. The terms xe2x80x9csulfamylxe2x80x9d, xe2x80x9caminosulfonylxe2x80x9d and xe2x80x9csulfonamidylxe2x80x9d, denote NH2O2Sxe2x80x94.
The term xe2x80x9ccarbonylxe2x80x9d, whether used alone or with other terms, such as xe2x80x9calkoxycarbonylxe2x80x9d, denotes 
The terms xe2x80x9ccarboxyxe2x80x9d or xe2x80x9ccarboxylxe2x80x9d, whether used alone or with other terms, such as xe2x80x9ccarboxyalkylxe2x80x9d, denotes xe2x80x94CO2H. The term xe2x80x9ccarboxyalkylxe2x80x9d embraces alkyl radicals substituted with a carboxy radia. More preferred are xe2x80x9clower carboxyalkylxe2x80x9d radicals which embrace carboxy-substituted lower alkyl radicals as defined above. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term xe2x80x9calkoxycarbonylxe2x80x9d means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are xe2x80x9clower alkoxycarbonylxe2x80x9d radicals with alkyl portions having one to six carbons. Examples of such lower alkoxycarbonyl (ester) radicals include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The term xe2x80x9calkoxycarbonylalkylenexe2x80x9d embraces alkylene radicals substituted with an alkoxycarbonyl radical as defined above. More preferred are xe2x80x9clower alkoxycarbonylalkylenexe2x80x9d radicals with alkylene portions having one to six carbons. Examples of such lower alkoxycarbonylalkylene radicals include substituted or unsubstituted methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl and ethoxycarbonylethyl. The term xe2x80x9calkylcarbonylxe2x80x9d, includes radicals having alkyl radicals, as defined herein, attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, and pentylcarbonyl. The term xe2x80x9caralkylxe2x80x9d embraces aryl-substituted alkyl radicals. Preferred are xe2x80x9clower aralkylxe2x80x9d radicals having branched or unbranched lower alkyl portions containing one to six carbon atoms. Examples include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable. The term xe2x80x9caryloxyxe2x80x9d embraces aryl radicals attached through an oxygen atom to other radicals. The term xe2x80x9caralkoxyxe2x80x9d embraces aralkyl radicals attached through an oxygen atom to other radicals.
The term xe2x80x9caminoalkylxe2x80x9d embraces alkyl radicals substituted with amino radicals. More preferred are xe2x80x9clower aminoalkylxe2x80x9d radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like. The term xe2x80x9calkylaminoxe2x80x9d denotes amino groups which are substituted with one or two alkyl radicals. Preferred are xe2x80x9clower alkylaminoxe2x80x9d radicals having alkyl portions having one to six carbon atoms. Suitable lower alkylamino may be monosubstituted N-alkylamino or disubstituted N,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term xe2x80x9carylaminolxe2x80x9d denotes amino groups which are substituted with one or two aryl radicals, such as N-phenylamino. The xe2x80x9carylaminoxe2x80x9d radicals may be further substituted on the aryl ring portion of the radical. The term xe2x80x9caminocarbonylxe2x80x9d denotes an amide group of the formula xe2x80x94C(xe2x95x90O)NH2. The term xe2x80x9calkylaminocarbonylxe2x80x9d denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals on the amino nitrogen atom. Preferred are xe2x80x9cN-alkylaminocarbonylxe2x80x9d and xe2x80x9cN,N-dialkylaminocarbonylxe2x80x9d radicals. More preferred are xe2x80x9clower N-alkylaminocarbonylxe2x80x9d and xe2x80x9clower N,N-dialkylaminocarbohylxe2x80x9d radicals with lower alkyl portions as defined above. The term xe2x80x9calkylcarbonylaminolxe2x80x9d embraces amino groups which are substituted with an alkylcarbonyl radical. More preferred alkylcarbonylamino radicals are xe2x80x9clower alkylcarbonylaminoxe2x80x9d having lower alkylcarbonyl radicals as defined above attached to amino radicals. The term xe2x80x9calkylaminoalkylenexe2x80x9d embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical.
The additional terms used to describe the substituents of the pyrazole ring and not specifically defined herein are defined in a similar manner to that illustrated in the above definitions. As above, more preferred substituents are those containing xe2x80x9clowerxe2x80x9d radicals. Unless otherwise defined to contrary, the term xe2x80x9clowerxe2x80x9d as used in this application means that each alkyl radical of a pyrazole ring substituent comprising one or more alkyl radicals has one to about six carbon atoms; each alkenyl radical of a pyrazole ring substituent comprising one or more alkenyl radicals has two to about six carbon atoms; each alkynyl radical of a pyrazole ring substituent comprising one or more alkynyl radicals has two to about six carbon atoms; each cycloalkyl or cycloalkenyl radical of a pyrazole ring substituent comprising one or more cycloalkyl and/or cycloalkenyl radicals is a 3 to 8 membered ring cycloalkyl or cycloalkenyl radical, respectively; each aryl radical of a pyrazole ring substituent comprising one or more aryl radicals is a monocyclic aryl radical; and each heterocyclyl radical of a pyrazole ring substituent comprising one or more heterocyclyl radicals is a 4-8 membered ring heterocyclyl.
The present invention comprises the tautomeric forms of compounds of Formulas I-VIII. As illustrated below, the pyrazoles of Formula Ixe2x80x2 and Ixe2x80x3 are magnetically and structurally equivalent because of the prototropic tautomeric nature of the hydrogen: 
The present invention also comprises compounds of Formula I-VIII having one or more asymmetric carbons. It is known to those skilled in the art that those pyrazoles of the present invention having asymmetric carbon atoms may exist in diastereomeric, racemic, or optically active forms. All of these forms are contemplated within the scope of this invention. More specifically, the present invention includes enantiomers, diastereomers, racemic mixtures, and other mixtures thereof.
The present invention comprises a pharmaceutical composition for the treatment of a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis, comprising a therapeutically-effective amount of a compound of Formula I-VIII, or a therapeutically-acceptable salt or tautomer thereof, in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
The present invention also comprises a therapeutic method of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having or susceptible to such disorder or condition with a therapeutically-effective amount of a compound of Formula I, or a therapeutically-acceptable salt or tautomer thereof, wherein
R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene,. cycloalkenylalkylene, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, heterocyclylalkylene, alkoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, mercaptoalkyl, mercaptoaryl, mercaptoheterocyclyl, alkylthioalkylene, arylthioalkylene, amino, alkylamino, arylamino, aminoalkyl, aminoaryl, alkylaminoalkylene, and heterocyclylalkylene; and
Q is selected from oxy, thio, alkylene, alkenylene, alkynylene, sulfinyl, sulfonyl, 
xe2x80x83wherein 
represents a four to eight membered ring heterocyclylidenyl comprising one or more heteroatoms selected from oxygen, sulfur and nitrogen; and
wherein n is an integer from 1 to 7; and
R2 is aryl optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heterocyclyloxy, aralkoxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, amino, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, aminoalkyl, aminocarbonyl, cyano, hydroxyl, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, formyl, nitro, nitroalkyl, alkylcarbonylamino, arylcarbonylamino, haloalkylsulfinyl, haloalkylsulfonyl, alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, and haloalkyl; and
R3 is heteroaryl optionally substituted with one or more radicals independently selected from halo, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, aminocarbonyl, cyano, hydroxyl, alkoxycarbonyl, formyl, aralkyl, aralkyloxy, aralkylthio, aralkylamino, aminosulfonyl, alkylamino, nitro, arylamino, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl and alkylcarbonyl; and
R4 is selected from hydrido, alkyl, aryl, haloalkyl, heterocyclyl, cycloalkyl, alkenyl, cycloalkenyl, alkoxy, alkylthio, arylthio, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkylene, heterocyclylalkyl, amino, alkylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, heterocyclylaminoalkyl, and aminoheterocyclylamino; wherein the aryl, heterocyclyl, cycloalkyl, cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, amino, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aralkoxy, haloalkyl, and alkylamino; and wherein the amino radicals of the heterocylcylalkylamino and heterocylcylaminoalkyl group are optionally substituted with one or more alkyl; and
R6 is selected from hydrido, alkyl, alkenyl, and alkynyl; and
R7 and R8 are independently selected from hydrido, alkyl, alkenyl, and alkynyl, or together form a carbocyclic or heterocyclic ring having three to eight members; and
R9 is selected from hydrido, alkyl, alkenyl, and alkynyl; and
R10 is selected from hydrido, alkyl, alkenyl, and alkynyl; and
R11 is selected from hydrido, alkyl, alkenyl, and alkynyl; and
R12 is selected from hydrido and alkyl; or a pharmaceutically-acceptable salt or tautomer thereof.
Also included in the family of compounds of Formula I are the pharmaceutically-acceptable salts thereof. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, xcex2-hydroxybutyric, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts and organic salts. More preferred metallic salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts and other physiological acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, tromethamine, diethylamine, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formulas I-VIII by reacting, for example, the appropriate acid or base with the compound of Formulas I-VIII.
General Synthetic Procedures
The compounds of the invention can be prepared according to the following procedures of Schemes I-X wherein the R1-R11 and Q substituents are as previously defined for compounds of Formula I or II except where noted. 
General Synthetic Scheme I shows the preparation of the pyrazoles of the present invention where R1 is hydrido and where Q is a saturated alkylene bridging radical 5 or an unsaturated alkenylene bridge 4. A propenyl derivative 1 is condensed with heterocyclic ketones and aldehydes 2 by the Knoevenagle condensation to give the pictured dienone 3. The dienone 3 is condensed, such as with tosyl hydrazide in boiling acetic acid, to yield the corresponding pyrazole derivative 4 of the present invention (where R1 is hydrido, Q is alkenylene). Other compounds of the invention 5 (where Q is alkylene) can be prepared from pyrazole 4 via hydrogenation of the double bond, such as with hydrogen gas and palladium on carbon in a suitable solvent, such as methanol. 
General Synthetic Scheme II shows the preparation of a subset of the pyrazoles of the present invention (where R2 is optionally substituted phenyl, R3 is optionally substituted pyridyl, and R4 is hydrido) where Q is a saturated alkylene bridging radical 11 or an unsaturated alkenylene bridge 10. A cinnamic ester 6 is alkylated with the anion of 4-picoline 7, such as by treatment with lithium hexamethyldisilazide (or other suitable base, such as sodium hydride) to the pictured enone 8. Reaction of the enone 8 with dimethylformamide dimethyl acetal gives the pictured vinylamine 9, which upon reaction with a suitable hydrazine yields the pyrazole 10 having an unsaturated alkenylene bridging radical. The unsaturated pyrazole 10 can be reduced to the corresponding saturated pyrazole 11, such as with hydrogen gas in the presence of palladium on carbon. 
General Synthetic Scheme III shows the preparation of a subset of the pyrazoles of the present invention (where R1 is hydrido, R2 is optionally substituted phenyl, R3 is optionally substituted pyridyl, R4 is hydrido) where Q is a carbonyl radical 15, a hydroxy-substituted alkylene bridge 16, or a saturated methylene bridging radical 17. Suitable acetophenone derivatives 12 are condensed with optionally substituted pyridines 13 in the presence of base to form enones 14. Cyclization of enone 14, such as with trimethylsilyldiazomethane, according to the published procedure of Aoyama, et al. (Chem. Pharm. Bull., 37, 253-256 (1989)) gives the pictured pyrazole-ketone 15. Other compounds of the invention are produced from the ketone 15, such as by reduction with sodium borohydride in methanol to form the alcohols 16. The alcohols 16 may be hydrogenolyzed by the action of hydrogen gas and palladium on carbon to form the pyrazoles 17 (where Q is methylene). 
General Synthetic Scheme IV shows the preparation of the pyrazoles of the present invention where R1 is alkyl or substituted alkyl. The pyrazole derivatives 18 can be alkylated at pyrazole position 1 with a suitable base, such as sodium hydride or potassium carbonate, in a suitable solvent, such as dimethylformamide, to yield the corresponding alkylated pyrazole derivatives 19. 
General Synthetic scheme V shows the preparation of a subset of the pyrazoles of the present invention where Q is an amide bridging radical. Ester 20 (prepared as set forth in Scheme VI) is hydrolyzed to the corresponding acid, then converted to an acid halide, for example by treatment with thionyl chloride. The acid halide is treated with a suitable alkali azide, such as sodium azide, and the resulting azide heated to effect the Curtius rearrangement to isocyanate 21. Isocyanate 21 is hydrolyzed with aqueous acid to yield free amine 22, which can be optionally alkylated to introduce the R6 substitution. Amine 22 is then acylated with a suitable aromatic active ester or acid halide 23 (preferably an aromatic active ester or acid chloride) to give pyrazoles 24. 
General Synthetic Scheme VI shows the preparation of a subset of the pyrazoles of Formula I where Q is an amide bridging radical. Optionally substituted 4-picoline 7 is deprotonated with a strong base, such as lithium hexamethyldisilazide, and acylated, for example, with oxalate ester 25 to give pyruvate 26. Pyruvate 26 is reacted with dimethylformamide dimethyl acetal to give an intermediate vinyl amine that is reacted with an optionally substituted hydrazine to give pyrazole ester 27. Pyrazole ester 27 is treated with aniline 28, under the influence of heat, to give pyrazole 29 wherein R4 is preferably hydrido. Alternatively, pyrazole ester 27 instead can be hydrolyzed to an intermediate acid which is then coupled to aniline 28 using a conventional amide coupling reaction (such as the coupling reaction of pyrazole ester 27 with dicyclohexylcarbodiimide).
Pyruvate 26 also may be treated with a halogenating agent, such as N-chlorosuccinimide, to yield an intermediate haloketone that is then reacted with thiosemicarbazide 30 to form pyrazole 31. Pyrazole 31 is aminated with aniline 28 using the procedure described above to produce aminopyrazole 32 wherein R1 is hydrido, R4 is xe2x80x94NR15R16, and R15 and R16 are, for example, hydrogen or alkyl, or together with the nitrogen atom to which they are attached form a 4 to 8 membered ring heterocyclyl comprising at least one heteroatom selected from oxygen, sulfur and nitrogen. The R1 hydrido of aminopyrazole 32 can be replaced with other substituents as shown, for example, in Scheme IV. 
General Synthetic Scheme VII shows the preparation of a subset of the pyrazoles of Formula I where Q is an ethanone bridging radical. Ester 33 (prepared as set forth in Scheme VI) is treated with a Grignard reagent 34 to produce pyrazole 35. Ester 33 may be suitably protected, employing protecting groups known to those skilled in the art, to efficiently carry out this transformation. 
General Synthetic Scheme VIII shows the preparation of a subset of the pyrazoles of Formula I where Q is a cyclic bridging radical. Optionally substituted 4-picoline 7 is deprotonated with a strong base, such as lithium hexamethyldisilazide, and acylated with cyclic ester 36 to give ketone 37. Ketone 37 is reacted with dimethylformamide dimethyl acetal to give intermediate vinyl amine that is reacted with optionally substituted hydrazine to give pyrazole 38 wherein R4 is hydrido.
Alternatively, ketone 37 can be halogenated to form an intermediate haloketone that can be reacted with optionally substituted thiosemicarbazide 30 to give pyrazole 39 wherein R1 is hydrido, R4 is xe2x80x94NR15R16, and R15 and R16 are as defined for Scheme VI. 
General Synthetic Scheme IX shows the preparation of a subset of the pyrazoles of Formula I where Q is a urea bridging radical. Isocyanate 40 (prepared as set forth in Scheme V) is reacted with optionally substituted aniline 41 to give urea 42. 
General Synthetic Scheme X shows the preparation of a subset of the pyrazoles of Formula I where Q is a sulfonamide bridging radical. Amine 43 (prepared as set forth in Scheme V) is reacted with an optionally substituted aromatic sulfonyl halide 44, preferably sulfonyl chloride, to give pyrazole 45.
Within Formula I there is another subclass of compounds of interest represented by Formula III: 
Compounds of Formula III can be prepared in accordance with the chemistry set forth above (particularly Scheme V) and include the following compounds: 
Within Formula I there is another subclass of compounds of interest represented by Formula IV: 
Compounds of Formula IV can be prepared in accordance with the chemistry set forth above (particularly Scheme VI) and include the following compounds: 
Within Formula I there is another subclass of compounds of interest represented by Formula V: 
Compounds of Formula V can be prepared in accordance with the chemistry set forth above (particularly Scheme VII) and include the following compounds: 
Within Formula I there is another subclass of compounds of interest represented by the Formula VI: 
Compounds of Formula VI can be prepared in accordance with the chemistry set forth above (particularly Scheme VIII) and include the following compounds: 
Within Formula I there is another subclass of compounds of interest represented by Formula VII: 
Compounds of Formula VII can be prepared in accordance with the chemistry set forth above (particularly Scheme IX) and include the following compounds: 
Within Formula I there is another subclass of compounds of interest represented by Formula VIII 
Compounds of Formula VIII can be prepared in accordance with the chemistry set forth above (particularly Scheme X) and include the following compounds: 
In the above compounds of Formula III, IV, V, VI, VII and VIII, the substituents R1, R4, R5, R6, R7, R8, R9, R10 and R11 are as previously defined for the compounds of Formula I, and substituent X1 encompasses the optional substituents previously defined for the R2 aryl group of the compounds of Formula I. In addition to the specific compounds illustrated above, other specific compounds of Formula III, IV, V, VI, VII and VIII of particular interest include those wherein the R4 hydrogen or methylpiperazinyl substituent is replaced with propargylamino, substituted or unsubstituted piperidinyl, or substituted or unsubstituted morpholinyl.
The following examples contain detailed descriptions of the methods of preparation of compounds of Formula I-VIII. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures. In some cases, the assigned structures were confirmed by nuclear Overhauser effect (NOE) experiments.
The following abbreviations are used:
MeOHxe2x80x94methanol
Pd/Cxe2x80x94palladium on carbon
RTxe2x80x94room temperature
DTTxe2x80x94dithiotreitol
dH2Oxe2x80x94distilled water
PBSxe2x80x94phosphate buffered saline
NaClxe2x80x94sodium chloride
KClxe2x80x94potassium chloride
Na2HPO4xe2x80x94sodium phosphate
KH2PO4xe2x80x94potassium phosphate
PMSFxe2x80x94phenylmethylsulfonyl fluoride
EDTAxe2x80x94ethylene diamine tetraacetic acid
HEPESxe2x80x94N-[2-hydroxyethyl]piperazine-Nxe2x80x2-[2-ethanesulfonic acid]
DMSOxe2x80x94dimethyl sulfoxide
SOCl2xe2x80x94thionyl chloride
NaN3xe2x80x94sodium azide
KOHxe2x80x94potassium hydroxide
Etxe2x80x94ethyl
LiHMDSxe2x80x94lithium hexamethyldisilazide
THFxe2x80x94tetrahydrofuran
DMFxe2x80x94dimethyl formamide
hxe2x80x94hour
minxe2x80x94minutes